Efficacy and safety of Chinese herbal medicine in treating postcholecystectomy diarrhea: A systematic review and meta-analysis

Background: Postcholecystectomy diarrhea (PCD) is among the most distressing and well-known clinical complications of cholecystectomy. Despite various available treatment options, clinical outcomes are greatly limited by unclear pathophysiological mechanisms. Chinese herbal medicine (CHM) is widely used as a complementary and alternative therapy for the treatment of functional diarrhea. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of CHM for the treatment of PCD. Methods: Electronic database searches were conducted using the Cochrane Library, PubMed, Web of Science, Embase, Wanfang Data, China National Knowledge Infrastructure, and the Chinese Scientific Journal Database. All RCTs on CHMs for managing patients with PCD were included. The meta-analysis was performed using RevMan 5.4 software. Results: The present meta-analysis included 14 RCTs published between 2009 and 2021 in China. The primary findings indicated that CHM had a higher total efficacy and cure rate as a monotherapy for PCD (P < .00001). Two trials reported the scores of the main symptoms with statistically significant differences in stool nature (P < .00001), defecation frequency (P = .002), and abdominal pain and bloating (P < .00001). In addition, CHM reduced CD3+ and CD4+ levels more effectively in terms of T lymphocyte subset determination (P < .00001). The main symptoms of PCD in traditional Chinese medicine (TCM) are splenic deficiency and liver stagnation. All treatments were used to strengthen the spleen and (or) soothing the liver. Conclusion: CHM had a favorable effect on PCD. No adverse events were observed. Larger, high-quality RCTs are warranted to draw definitive conclusions and standardize treatment protocols.


Introduction
Cholecystectomy remains the gold-standard method of therapy because of the increasing incidence of benign gallbladder diseases, mainly cholecystitis and gallstones. [1]Moreover, the laparoscopic approach has been widely used as the standard technique because it has significantly lower morbidity and mortality rates than open surgery. [2,3]Nevertheless, postcholecystectomy syndrome (PCS) may occur weeks or months after cholecystectomy and manifests with clinical symptoms such as diarrhea, abdominal pain, and bloating.In particular, postcholecystectomy diarrhea (PCD) is a relatively well-known clinical complication [4,5] characterized by a prolonged course, recurrence, and persistence, which significantly affects the quality of life of patients and even causes a portion of the population to develop disability. [6]PCD is highly prevalent and protracted.A previous review reported an average prevalence of 13.3% (2.1%-57.2%),although with the limitation of various follow-up times. [4]The 2020 Canadian Chronic Diarrhea Guidelines highlight cholecystectomy as a risk factor for chronic diarrhea. [7]In addition, Ribas et al [8] found that >50% of patients had abnormal bowel habits after cholecystectomy, of which 23% had unrelieved symptoms after 6 months.
The pathophysiological mechanisms underlying PCD are not well understood.Despite different treatment options available, clinical outcomes are unsatisfactory.Due to their expanding role in the primary management of gastrointestinal diseases, dietary interventions are recommended. [9]However, a recent study showed that a low-lipid diet did not improve the symptoms in patients with PCD. [8]In addition, owing to the lack of sufficient clinical data and negative publicity of media reports, there is no The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.This meta-analysis did not require ethical approval or patient consent to participate.
a Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Xicheng District, Beijing, P.R. China.
conclusive evidence of the true clinical effect of dietary interventions. [10]In addition, nearly a quarter of patients with PCD take different types of bile-binding drugs, of which colestyramine is the most frequently used.However, a systematic review including a small number of studies showed that the short-and longterm responses to colestyramine in the postcholecystectomy group were 47.63% and 36.2%,respectively.Notably, only 47.52% of patients with a clear diagnosis of severe bile acid diarrhea had a higher short-term response, [11] and the long-term response was largely limited by poor tolerance. [12]Fecal microbiome transplantation is a promising therapy for irritable bowel syndrome (IBS) that involves rebuilding the intestinal microbiota, restoring intestinal function, and repairing the intestinal mucosa. [13]Nevertheless, currently, randomized controlled trials (RCTs) showed conflicting results. [14,15]In addition, probiotics are not recommended because of higher-quality evidence and differences in the composition of probiotics. [10]raditional Chinese medicine (TCM) has long used a combination of herbal remedies and multiple targets based on symptom patterns. [16,17]The variety of Chinese herbs is rich, with the advantages of being well tolerated, simple to produce, and economical.Indeed, Chinese herbal medicine (CHM) was preliminarily acknowledged for functional diarrhea in the clinic.Considering the disabling nature and the lack of effective treatments for PCD, CHM has been widely used as a complementary and alternative therapy.However, systematic analyses of CHM in PCD are lacking.Thus, we conducted a meta-analysis of RCTs to evaluate the efficacy and safety of CHM in treating PCD and attempted to provide a protocol for clinical practice.

Criteria for including studies
All RCTs on CHMs for managing patients with PCD were included.Specifically, studies on CHMs versus Western medicines or blank controls were included.The outcomes included the total effective rate, cure rate, T lymphocyte subset determination, and scores for the main symptoms.

Criteria for excluding studies
Studies on other main treatments were excluded.Non-RCTs, non-AIS, clinical experience, trials with fewer than 10 patients, cross-sectional studies, case reports, comments, and reviews were excluded from the analysis.

Database searches
Electronic database searches were conducted from database inception to October 2022, including Cochrane Library, PubMed, Web of Science, Embase, Wanfang Data, China National Knowledge Infrastructure, and Chinese Scientific Journal Database.The combinations of MeSH Terms and relevant keywords were as follows: "Cholecystectomy" (MeSH Terms) AND "Diarrhea" (MeSH Terms) OR "Postcholecystectomy Syndrome" (MeSH Terms).To comprehensively include the literature, we manually screened the target literature regarding CHM for managing patients with PCD.Additionally, a search strategy was determined for each database.The language was restricted to English or Chinese, with no limitations on the subheadings.We searched the reference lists of the identified papers to explore other studies, and trials not covered in the aforementioned databases were additionally searched once they were identified.Duplicate studies were excluded after reviewing the abstracts and full texts.This study mainly referred to the 12 reporting guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for the metaanalysis of intervention trials. [18] 4

. Data collection and analysis
Data processing was independently managed by 2 authors using Endnote X8 software, and disagreements were resolved by a third author.The information for each eligible study included: descriptive statistics such as author information, publication year and country, data sources, and sample sizes; intervention characteristics such as detailed CHM and treatment course; type of clinical study design and methods of randomization and blinding; and information on outcomes such as outcomes of interest, follow-up duration, and adverse events.The total effective rate was calculated as the ratio of the number of patients with positive outcomes to the total number of patients, whereas the cure rate was the ratio of the number of cured patients to the total number of individuals.If necessary, we contacted the authors of the included studies for additional original data.According to the guiding principles of clinical research on new TCM: Trial, [19] clinical symptom scores, including stool properties, defecation frequency, and abdominal pain and bloating, were observed in the 2 groups.A score of 0 was classified as asymptomatic, 1 as mild, 2 as moderate, and 3 as severe.Lower scores indicate less severe clinical symptoms.

Statistical analysis
The meta-analysis was performed using RevMan 5.4 software.Statistical heterogeneity was evaluated using the chi-square and I 2 tests.An I 2 value of <25% indicated low heterogeneity and that <50% indicated moderate heterogeneity.A fixed-effects model was used.Otherwise, an I 2 value >50% indicated significant heterogeneity, and a random-effects model was adopted.Standardized mean differences (SMDs) of 95% confidence intervals (CIs) were used for different measurement methods.If significant heterogeneity was observed, a sensitivity analysis was performed.

Study characteristics
The present meta-analysis included 14 RCTs published between 2009 and 2021 in China.All studies focused on the efficacy of independent CHM in the treatment of PCD compared to the control group.The CHM used in the selected studies had great heterogeneity, but all were consistent with the syndrome type of spleen deficiency and the liver stagnation pattern.Patients were treated for 2 weeks, 1 month, 6 weeks, 2 months, and 3 months in 2, 2, 1, 5, and 2 studies, respectively.In all studies, the types and frequencies of CHM were not completely consistent, and the Western medicine groups were different.Specifically, patients were treated with Tongxie Yaofang in 5 studies, Shenling Baizhu Powder in 4 studies, Sijunzi Decoction in 2 studies, and all the others including Buzhong Yiqi Decoction, Jianpi Yiqi Decoction, Xiaoyao Pingwei Decoction, Jianpi Zaoshi Decoction, Sishen Pill, Gegen Qinlian Decoction, Lizhong Decoction, and Xiexie Decoction appeared only in 1 study.The drugs used in the control groups were Bacillus licheniformis capsules, compound digestive enzyme capsules, montmorillonite powder, live combined bifidobacteria and lactobacillus tablets, Clostridium butyricum tablets, pinaverium bromide tablets, and bifid triple-viable capsules dissolved in the intestines.Treatment initiation ranged from 2 days to 12 months.The most commonly used CHM consists of Tongxie Yaofang and Shenling Baizhu Powder, which are used for treating liver stagnation and spleen deficiency patterns of syndrome, respectively.All trials reported a total effective rate, 13 trials reported a cure rate, 3 reported T lymphocyte subset determination, and 2 reported the scores of the main symptoms.All included studies were based on the criteria of diagnosis and therapeutic effect of diseases and syndromes in TCM to evaluate the efficacy of drugs, especially CHM, for PCD.

Risk of bias
Of the 14 included studies, all but one were considered to have a low risk of bias.Random sequence generation was reported in 6 studies and allocation concealment was reported in 3 studies.Only 1 study had a high risk of bias in random sequence generation and allocation concealment.As shown in Figure 2, blinding of participants and personnel, blinding of the outcome assessment, incomplete outcome data, selective reporting, and other biases were not observed in any of the 14 studies.

Outcome measures
3.4.1.Total effective rate.Fourteen trials, including 901 subjects, reported the total efficacy rate.As shown in Figure 3, a statistically significant difference was found (P < .00001),and a fixed-effects model was used because of mild heterogeneity (I 2 = 24%).These results demonstrate a higher efficacy rate in the CHM group.

Cure rate.
Thirteen trials including 842 participants reported cure rates.As shown in Figure 4, a statistically significant difference was found (P < .00001),and a fixed-effects model was used (I 2 = 0%).The results showed a higher cure rate in the CHM group.
A random-effects model was used only for defection frequency owing to severe heterogeneity (I 2 = 77%), whereas a fixed-effects model was used in the remaining 2 terms without heterogeneity (I 2 = 0%).

Sensitivity analysis
Sensitivity analysis was conducted to evaluate the effect of individual studies on the overall outcome by sequentially removing the studies.Regarding CD 8

+
, there was a substantial change in the results and heterogeneity when the study by Yao was removed (P < .00001,I 2 = 0%).

Publication bias
The total effective rate was the common outcome index of the 14 included RCTs and was also the main indicator.Therefore, an outcome index was used to create a funnel plot for detecting publication bias (Fig. 7).Visual inspection of the funnel plots revealed symmetry, suggesting that there was no publication bias.

Discussion
Diarrhea is one of the most frequently reported postoperative complications of cholecystectomy. [34]Although multiple possible avenues have been proposed, the multifactorial mechanisms underlying the development of PCD remain unclear.[37] Nevertheless, Laura et al [11] proposed no significant relationship between the date of cholecystectomy and the onset of bile acid diarrhea.Therefore, current treatments mainly focus on symptom relief. [17]onsidering its disabling nature and the lack of effective treatment for PCD, CHM has been widely used as a complementary and alternative therapy based on the pattern of symptoms.The variety of CHM is rich, with the advantages of being welltolerated, simple to produce, and economical. [38]Here, we conducted a meta-analysis of RCTs on the efficacy and safety of CHM for the treatment of PCD.
Our primary findings indicate that CHM has a higher total effectiveness and cure rate as a monotherapy for PCD.Two trials reported the scores for the main symptoms.Statistically significant differences were observed in the nature of stool, defecation frequency, abdominal pain, and bloating.The main PCD syndrome types in TCM are spleen deficiency and liver stagnation.Generally, the liver and gallbladder are perfectly sympathetic to    In addition, the transport function of the spleen relies on the normal drainage function of the liver.After cholecystectomy, the gallbladder loses its ability to function, which leads to liver qi stagnation, transverse invasion into the spleen, and weakness of the spleen transport function, thus causing diarrhea.Among the included studies, 6 used Tongxie Yaofang, a representative CHM, for diarrhea with pain caused by spleen deficiency and a liver stagnation pattern.Tongxie Yaofang strengthens the spleen, eliminates dampness, soothes the liver, regulates qi, and relieves diarrhea. [39]Several reports have confirmed its effectiveness and few adverse reactions in the treatment of gastrointestinal dysfunction, including diarrhea-predominant irritable bowel syndrome (IBS-D) [40] and ulcerative colitis. [41]ongxie Yaofang may improve IBS-D by inhibiting apoptosis and inflammatory responses, regulating intestinal flora, relieving visceral hypersensitivity, and enhancing the intestinal mucosal barrier. [5,42]Four studies used Shenling Baizhu Powder, a classical and widely used prescription for managing spleen deficiency diarrhea.Splenic deficiency syndrome is closely related to immune system dysfunction, and CHM may treat splenic deficiency-induced diarrhea by adjusting the absorption function of the intestinal mucosa, improving the inflammatory response, and regulating immunity. [43]n addition, CHM may reduce CD 3 + and CD 4 + T lymphocyte subsets more effectively.Increasing evidence suggests that the immune system plays a vital role in diarrheal pathogenesis. [38]T-lymphocyte subsets are important indicators of cellular immune function.CD 3 + is an indicator of the overall immune status of cells and the total number of T lymphocytes.Based on their phenotypes, T lymphocytes were divided into CD 4 + and CD 8 + subgroups.CD 4 + cells are mainly helper T lymphocytes, whereas CD 8 + cells are mainly inhibitory and cytotoxic T lymphocytes, which dynamically regulate immunity.Patients with IBS may have reduced CD 3 + and CD 4 + counts, which leads to immune function disorders, the release of injurious immune factors, cell damage, persistent inflammatory reactions, and consequent dysfunction of sensory, secretory, and motor functions of the gut. [44]Therefore, we speculate that CHM has the desired holistic and bidirectional immune regulatory functions in PCD.However, the specific mechanism of CHM in PCD remains unclear, and further studies are warranted.

Limitations
To the best of our knowledge, this is the first meta-analysis to evaluate the efficacy of CHM in the treatment of PCD.However, this study has some limitations.First, most studies lacked details on random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment, which may have contributed to the low general level of evidence.Second, considering the individualized prescription characteristics of CHM, there were various CHM prescriptions in the present study.In addition, prescriptions may be modified based on changes in symptoms.These findings are not conducive to the methodological quality of RCTs. [17]Third, the follow-up and treatment times were too heterogeneous to be standardized.Finally, we used outcome measurements that are not commonly used internationally.There is no standardized definition of PCD.However, it is noteworthy that most studies referred to the criteria compiled by TCM experts in China, and we still expected future studies to apply the internationally validated questionnaires for reproducibility.Overall, larger, high-quality RCTs are required, and the study of the mechanisms of CHM and PCD could promote clinical progress.

Conclusion
Oral CHM is well tolerated, simple, and economical with a desired curative effect, which is worthy of clinical promotion.The results of the present meta-analysis revealed that CHM had a more favorable effect on PCD.No adverse events were observed.However, considering the heterogeneity and generally low quality of the included RCTs, further research is required to draw definitive conclusions and establish standardized treatment protocols.

Figure 1 .
Figure 1.Flow diagram of the selection process for the studies included in the meta-analysis.

Figure 3 .
Figure 3. Forest plot showing the effect of Chinese herbal medicine vs controls on the total effective rate in the treatment of postcholecystectomy diarrhea (CI = confidence interval, M-H = Mantel-Haenszel).

Figure 4 .
Figure 4. Forest plot showing the effect of Chinese herbal medicine vs controls on the cure rate in the treatment of postcholecystectomy diarrhea (CI = confidence interval, M-H = Mantel-Haenszel).

Figure 5 .
Figure 5. Forest plot showing the effect of Chinese herbal medicine vs controls on the detection of T-lymphocyte subsets including CD 3 + (A), CD 4 + (B) and CD 8 +

Figure 6 .
Figure 6.Forest plot showing the effect of Chinese herbal medicine vs controls on the scores of main symptoms including stool nature (A), defecation frequency (B), abdominal pain and bloating (C) in the treatment of postcholecystectomy diarrhea (CI = confidence interval, IV = inverse variance).